Acute myeloid leukemia (WP5293)

Homo sapiens

Open in new tab Open in Newt (SBGN)
Download PNG Download SVG Download JSON Download GPML Learn more about Downloads
Acute Myeloid Leukemia is a cancer of the myeloid cell line of blood cells of the bone marrow. Rapid growth of cancer cells leads to the accumulation of neoplastic blasts in the node marrow, and interferes with the production of normal blood cells. AML develops as the consequence of a series of genetic changes. Two major types of changes have been described as crucial for leukemic transformation: 1. Disordered cell growth and up-regulation of cell survival genes. The most common of these activating events are in the RTK Flt3, in N-Ras and K-Ras, in Kit, and sometimes in other RTKs. 2. Alterations in transcription factors regulating hematopoietic differentiation. Transcription factor fusion proteins such as AML-ETO, PML-RARalpha or PLZF-RARalpha block myeloid cell differentiation by repressing target genes. Sometimes the transcription factors themselves are mutated. This description was adapted from KEGG (https://www.kegg.jp/pathway/map=map05221), Wikipedia (https://en.wikipedia.org/wiki/Acute_myeloid_leukemia) and Wolters Kluwer Up to Date (https://www.uptodate.com/contents/acute-myeloid-leukemia-molecular-genetics).

Authors

Kristina Hanspers and Eric Weitz

Activity

last edited

Discuss this pathway

Check for ongoing discussions or start your own.

Cited In

Are you planning to include this pathway in your next publication? See How to Cite and add a link here to your paper once it's online.

Organisms

Homo sapiens

Communities

Annotations

Cell Type Ontology

myeloid cell

Disease Ontology

bone marrow cancer

Pathway Ontology

acute myeloid leukemia pathway bone cancer pathway

Participants
Query Drugst.One

Label Type Compact URI Comment
Dasatinib Metabolite chebi:49375
Midostaurin Metabolite chebi:63452
Retinoic acid Metabolite chebi:15367
Arsenic trioxide Metabolite chebi:49900
PIP3 Metabolite chebi:16618
Radotinib Metabolite wikidata:Q15269680
Gilteritinib Metabolite wikidata:Q27077802
Sunitinib Metabolite chebi:38940
Lestaurtinib Metabolite wikidata:Q6531771
Crenolanib Metabolite wikidata:Q5184160
Sorafenib Metabolite chebi:50924
Ponatinib Metabolite chebi:78543
Quizartinib Metabolite chebi:90217
Ibrutinib Metabolite chebi:76612
Fostamatinib Metabolite wikidata:Q5473550
Entospletinib Metabolite wikidata:Q27077193
AKT3 GeneProduct ensembl:ENSG00000117020
AKT2 GeneProduct ensembl:ENSG00000105221
KIT GeneProduct ensembl:ENSG00000157404
FLT3-ITD GeneProduct ensembl:ENSG00000122025
GRB2 GeneProduct ensembl:ENSG00000177885
SOS1 GeneProduct ensembl:ENSG00000115904
RUNX1 GeneProduct ensembl:ENSG00000159216
SOS2 GeneProduct ensembl:ENSG00000100485
GLI1 GeneProduct ncbigene:2735
PIM1 GeneProduct ensembl:ENSG00000137193
HRAS GeneProduct ensembl:ENSG00000174775
KRAS GeneProduct ensembl:ENSG00000133703
NRAS GeneProduct ensembl:ENSG00000213281
ARAF GeneProduct ncbigene:369
RAF1 GeneProduct ensembl:ENSG00000132155
BRAF GeneProduct ensembl:ENSG00000157764
STAT3 GeneProduct ensembl:ENSG00000168610
STAT5A GeneProduct ensembl:ENSG00000126561
STAT5B GeneProduct ensembl:ENSG00000173757
PIK3CA GeneProduct ensembl:ENSG00000121879
PIK3CB GeneProduct ensembl:ENSG00000051382
PIK3CD GeneProduct ensembl:ENSG00000171608
PIK3R1 GeneProduct ensembl:ENSG00000145675
PIK3R2 GeneProduct ensembl:ENSG00000105647
PIK3R3 GeneProduct ensembl:ENSG00000117461
AKT1 GeneProduct ensembl:ENSG00000142208
CHUK GeneProduct ensembl:ENSG00000213341
IKBKB GeneProduct ensembl:ENSG00000104365
IKBKG GeneProduct ensembl:ENSG00000269335
BAD GeneProduct ensembl:ENSG00000002330
MTOR GeneProduct ensembl:ENSG00000198793
NFKB1 GeneProduct ensembl:ENSG00000109320
RELA GeneProduct ncbigene:5970
MAP2K1 GeneProduct ncbigene:5604
MAPK1 GeneProduct ncbigene:5594
MAPK3 GeneProduct ncbigene:5595
MAP2K2 GeneProduct ncbigene:5605
EIF4EBP1 GeneProduct ensembl:ENSG00000187840
RPS6KB2 GeneProduct ensembl:ENSG00000175634
RPS6KB1 GeneProduct ensembl:ENSG00000108443
PIM2 GeneProduct ensembl:ENSG00000102096
BCL2A1 GeneProduct ensembl:ENSG00000140379
CEBPE GeneProduct ensembl:ENSG00000092067
SPI1 GeneProduct ensembl:ENSG00000066336
RUNX1T1 GeneProduct ensembl:ENSG00000079102
PML GeneProduct ensembl:ENSG00000140464
RARA GeneProduct ensembl:ENSG00000131759
ZBTB16 GeneProduct ensembl:ENSG00000109906
CEBPA GeneProduct ensembl:ENSG00000245848
JUP GeneProduct ensembl:ENSG00000173801
CCND1 GeneProduct ensembl:ENSG00000110092
MYC GeneProduct ensembl:ENSG00000136997
PPARD GeneProduct ensembl:ENSG00000112033
DUSP6 GeneProduct ensembl:ENSG00000139318
CCNA2 GeneProduct ensembl:ENSG00000145386
CCNA1 GeneProduct ensembl:ENSG00000133101
LEF1 GeneProduct ensembl:ENSG00000138795
TCF7 GeneProduct ensembl:ENSG00000081059
TCF7L2 GeneProduct ensembl:ENSG00000148737
TCF7L1 GeneProduct ensembl:ENSG00000152284
CD14 GeneProduct ensembl:ENSG00000170458
FCGR1A GeneProduct ensembl:ENSG00000150337
ITGAM GeneProduct ensembl:ENSG00000169896
CSF1R GeneProduct ensembl:ENSG00000182578
PER2 GeneProduct ensembl:ENSG00000132326
CSF2 GeneProduct ensembl:ENSG00000164400
MPO GeneProduct ensembl:ENSG00000005381
IL3 GeneProduct ensembl:ENSG00000164399
FLT3-ITD immature form GeneProduct ensembl:ENSG00000122025

References

  1. Role of the transcription factor AML-1 in acute leukemia and hematopoietic differentiation. Lutterbach B, Hiebert SW. Gene. 2000 Mar 21;245(2):223–35. PubMed Europe PMC Scholia
  2. The aberrant fusion proteins PML-RAR alpha and PLZF-RAR alpha contribute to the overexpression of cyclin A1 in acute promyelocytic leukemia. Müller C, Yang R, Park DJ, Serve H, Berdel WE, Koeffler HP. Blood. 2000 Dec 1;96(12):3894–9. PubMed Europe PMC Scholia
  3. Common themes in the pathogenesis of acute myeloid leukemia. Alcalay M, Orleth A, Sebastiani C, Meani N, Chiaradonna F, Casciari C, et al. Oncogene. 2001 Sep 10;20(40):5680–94. PubMed Europe PMC Scholia
  4. The role of the AML1 transcription factor in leukemogenesis. Lorsbach RB, Downing JR. Int J Hematol. 2001 Oct;74(3):258–65. PubMed Europe PMC Scholia
  5. Transcription factor fusions in acute leukemia: variations on a theme. Scandura JM, Boccuni P, Cammenga J, Nimer SD. Oncogene. 2002 May 13;21(21):3422–44. PubMed Europe PMC Scholia
  6. Increased exchange current but normal Ca2+ transport via Na+-Ca2+ exchange during cardiac hypertrophy after myocardial infarction. Gómez AM, Schwaller B, Porzig H, Vassort G, Niggli E, Egger M. Circ Res. 2002 Aug 23;91(4):323–30. PubMed Europe PMC Scholia
  7. The myeloid master regulator transcription factor PU.1 is inactivated by AML1-ETO in t(8;21) myeloid leukemia. Vangala RK, Heiss-Neumann MS, Rangatia JS, Singh SM, Schoch C, Tenen DG, et al. Blood. 2003 Jan 1;101(1):270–7. PubMed Europe PMC Scholia
  8. Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations. Mizuki M, Schwable J, Steur C, Choudhary C, Agrawal S, Sargin B, et al. Blood. 2003 Apr 15;101(8):3164–73. PubMed Europe PMC Scholia
  9. New mechanisms of AML1 gene alteration in hematological malignancies. Roumier C, Fenaux P, Lafage M, Imbert M, Eclache V, Preudhomme C. Leukemia. 2003 Jan;17(1):9–16. PubMed Europe PMC Scholia
  10. Disruption of differentiation in human cancer: AML shows the way. Tenen DG. Nat Rev Cancer. 2003 Feb;3(2):89–101. PubMed Europe PMC Scholia
  11. The role of FLT3 in haematopoietic malignancies. Stirewalt DL, Radich JP. Nat Rev Cancer. 2003 Sep;3(9):650–65. PubMed Europe PMC Scholia
  12. Translocation products in acute myeloid leukemia activate the Wnt signaling pathway in hematopoietic cells. Müller-Tidow C, Steffen B, Cauvet T, Tickenbrock L, Ji P, Diederichs S, et al. Mol Cell Biol. 2004 Apr;24(7):2890–904. PubMed Europe PMC Scholia
  13. The PML-RARalpha fusion protein and targeted therapy for acute promyelocytic leukemia. Jing Y. Leuk Lymphoma. 2004 Apr;45(4):639–48. PubMed Europe PMC Scholia
  14. Normal and oncogenic forms of the receptor tyrosine kinase kit. Lennartsson J, Jelacic T, Linnekin D, Shivakrupa R. Stem Cells. 2005;23(1):16–43. PubMed Europe PMC Scholia
  15. Transcription profiling of C/EBP targets identifies Per2 as a gene implicated in myeloid leukemia. Gery S, Gombart AF, Yi WS, Koeffler C, Hofmann WK, Koeffler HP. Blood. 2005 Oct 15;106(8):2827–36. PubMed Europe PMC Scholia
  16. Signal transduction of oncogenic Flt3. Choudhary C, Müller-Tidow C, Berdel WE, Serve H. Int J Hematol. 2005 Aug;82(2):93–9. PubMed Europe PMC Scholia
  17. The molecular pathogenesis of acute myeloid leukemia. Steffen B, Müller-Tidow C, Schwäble J, Berdel WE, Serve H. Crit Rev Oncol Hematol. 2005 Nov;56(2):195–221. PubMed Europe PMC Scholia
  18. ATRA resolves the differentiation block in t(15;17) acute myeloid leukemia by restoring PU.1 expression. Mueller BU, Pabst T, Fos J, Petkovic V, Fey MF, Asou N, et al. Blood. 2006 Apr 15;107(8):3330–8. PubMed Europe PMC Scholia
  19. Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia. Martelli AM, Nyåkern M, Tabellini G, Bortul R, Tazzari PL, Evangelisti C, et al. Leukemia. 2006 Jun;20(6):911–28. PubMed Europe PMC Scholia
  20. The emerging role of Wnt signaling in the pathogenesis of acute myeloid leukemia. Mikesch JH, Steffen B, Berdel WE, Serve H, Müller-Tidow C. Leukemia. 2007 Aug;21(8):1638–47. PubMed Europe PMC Scholia
  21. Dysregulation of the C/EBPalpha differentiation pathway in human cancer. Koschmieder S, Halmos B, Levantini E, Tenen DG. J Clin Oncol. 2009 Feb 1;27(4):619–28. PubMed Europe PMC Scholia
  22. Mislocalized activation of oncogenic RTKs switches downstream signaling outcomes. Choudhary C, Olsen JV, Brandts C, Cox J, Reddy PNG, Böhmer FD, et al. Mol Cell. 2009 Oct 23;36(2):326–39. PubMed Europe PMC Scholia
  23. Comprehensive genomic screens identify a role for PLZF-RARalpha as a positive regulator of cell proliferation via direct regulation of c-MYC. Rice KL, Hormaeche I, Doulatov S, Flatow JM, Grimwade D, Mills KI, et al. Blood. 2009 Dec 24;114(27):5499–511. PubMed Europe PMC Scholia
  24. Targeting c-KIT (CD117) by dasatinib and radotinib promotes acute myeloid leukemia cell death. Heo SK, Noh EK, Kim JY, Jeong YK, Jo JC, Choi Y, et al. Sci Rep. 2017 Nov 10;7(1):15278. PubMed Europe PMC Scholia
  25. Targeting Tyrosine Kinases in Acute Myeloid Leukemia: Why, Who and How? Fernandez S, Desplat V, Villacreces A, Guitart AV, Milpied N, Pigneux A, et al. Int J Mol Sci. 2019 Jul 12;20(14):3429. PubMed Europe PMC Scholia
  26. GLI1 reduces drug sensitivity by regulating cell cycle through PI3K/AKT/GSK3/CDK pathway in acute myeloid leukemia. Zhou C, Du J, Zhao L, Liu W, Zhao T, Liang H, et al. Cell Death Dis. 2021 Mar 3;12(3):231. PubMed Europe PMC Scholia